부산대학교 도서관

Blood-derived monocytes are found at sites of inflammation as well as in solid tumors and atherosclerotic arteries. They are an abundant source of inflammatory eicosanoids such as prostaglandin E[sub 2] (PGE[sub 2]) and thromboxane A[sub 2], which are formed via arachidonic acid (AA) metabolism by cyclooxygenase-½ (COX-½). In vitro studies of inflammatory mediator production are conducted invariably in room air, which does not reflect the oxygen tensions found in monocyte-containing lesions, which are frequently hypoxic. In this work we examined the effects of hypoxia at levels reported in these lesions, on monocyte COX-2 expression, the related events that lead to eicosanoid synthesis, and relationships with tumor necrosis factor (TNF)-α synthesis. In fresh human monocytes exposed to hypoxia (1% O[sub 2]), there was an increase in COX-2 protein compared with cells in normoxia, and this was attributable to increased transcription and mRNA stability. However, the synthesis of PGE[sub 2] and thromboxane A[sub 2] was reduced in hypoxia and did not reflect the increased level of COX-2. Monocytes prelabeled with [³H]AA followed by lipopolysaccharide stimulation in the presence of hypoxia showed a reduced release of AA compared with cells in normoxia. In addition, hypoxia resulted in decreased phosphorylation of the p44/42 mitogen-activated protein kinase and of cytosolic phospholipase A[sub 2]. Hypoxia also increased TNF-α synthesis, which appeared to play a role in COX-2 expression, and the observed increase TNF-α synthesis appeared to result from reduced PGE[sub 2] synthesis. Overall, the results suggest the existence of an autocrine loop of regulation between monocyte eicosanoid and TNF-α production, which is dysregulated in hypoxia and establishes hypoxia as being an important environmental determinant of inflammatory mediator production. [ABSTRACT FROM AUTHOR]